Cross-reactive epitopes and their role in food allergy
Authors: Sandip D. Kamath, Merima Bublin, Katsumasa Kitamura, Teruaki Matsui, Komei Ito, Andreas L. Lopata
Journal: Journal of Allergy and Clinical Immunology (2023)

Allergenic cross-reactivity among food allergens complicates the diagnosis and management of food allergy. This can result in many patients being sensitized (having allergen-specific IgE) to foods without exhibiting clinical reactivity. Some food groups such as shellfish, fish, tree nuts, and peanuts have very high rates of cross-reactivity. In contrast, relatively low rates are noted for grains and milk, whereas many other food families have variable rates of cross-reactivity or are not well studied. Although classical cross-reactive carbohydrate determinants are clinically not relevant, α-Gal in red meat through tick bites can lead to severe reactions. Multiple sensitizations to tree nuts complicate the diagnosis and management of patients allergic to peanut and tree nut. This review discusses cross-reactive allergens and cross-reactive carbohydrate determinants in the major food groups, and where available, describes their B-cell and T-cell epitopes. The clinical relevance of these cross-reactive B-cell and T-cell epitopes is highlighted and their possible impact on allergen-specific immunotherapy for food allergy is discussed. Allergenic cross-reactivity among food allergens complicates the diagnosis and management of food allergy. This can result in many patients being sensitized (having allergen-specific IgE) to foods without exhibiting clinical reactivity. Some food groups such as shellfish, fish, tree nuts, and peanuts have very high rates of cross-reactivity. In contrast, relatively low rates are noted for grains and milk, whereas many other food families have variable rates of cross-reactivity or are not well studied. Although classical cross-reactive carbohydrate determinants are clinically not relevant, α-Gal in red meat through tick bites can lead to severe reactions. Multiple sensitizations to tree nuts complicate the diagnosis and management of patients allergic to peanut and tree nut. This review discusses cross-reactive allergens and cross-reactive carbohydrate determinants in the major food groups, and where available, describes their B-cell and T-cell epitopes. The clinical relevance of these cross-reactive B-cell and T-cell epitopes is highlighted and their possible impact on allergen-specific immunotherapy for food allergy is discussed. Allergenic cross-reactivity can be clinically manifest or irrelevant. In vitro diagnosis of food allergy and its management is often hampered by cross-reacting food proteins.1Cox A.L. Eigenmann P.A. Sicherer S.H. Clinical relevance of cross-reactivity in food allergy.J Allergy Clin Immunol Pract. 2021; 9: 82-99Abstract Full Text Full Text PDF PubMed Google Scholar,2Sinson E. Ocampo C. Liao C. Nguyen S. Dinh L. Rodems K. et al.Cross-reactive carbohydrate determinant interference in cellulose-based IgE allergy tests utilizing recombinant allergen components.PLoS One. 2020; 15e0231344Crossref PubMed Scopus (7) Google Scholar IgE binding to cross-reactive clinically irrelevant allergens results in false-positive results on in vitro diagnostic tests. However, unidentified sources of cross-reactive allergens of clinical relevance may lead to unintentional exposure and allergic reactions, posing a health risk for the affected individuals. The concept of cross-reactivity between related or unrelated allergen sources is extensively addressed in the literature. However, this information is often not accompanied with data on identifying specific allergens or epitopes. The most common view in the current literature is that cross-reactive allergenic proteins present with a high primary amino acid sequence identity of above 70%.3Bublin M. Breiteneder H. Cross-reactivities of non-homologous allergens.Allergy. 2020; 75: 1019-1022Crossref PubMed Scopus (7) Google Scholar However, relevant IgE-binding epitopes are often below 20 amino acids in length and allow for a much better assessment of allergenic cross-reactivity.4Matsuo H. Yokooji T. Taogoshi T. Common food allergens and their IgE-binding epitopes.Allergol Int. 2015; 64: 332-343Abstract Full Text Full Text PDF PubMed Google Scholar In addition, shared cross-reactive T-cell epitopes could explain some of the clinical desensitization to food allergens observed after successful pollen immunotherapy5Furci F. Ricciardi L. Plant food allergy improvement after grass pollen sublingual immunotherapy: a case series.Pathogens. 2021; 10: 1412Crossref PubMed Scopus (0) Google Scholar; however, the cross-reactive T-cell epitopes have been studied for very few allergens. Well-characterized cross-reactive B-cell and T-cell epitopes between food allergens will not only assist in developing more specific and accurate molecular diagnosis but also contribute to the development of lead candidates for targeted immunotherapy. In this review, we summarize the basic concepts of allergenic cross-reactivity, discuss about protein and carbohydrate epitopes, and provide an overview of the cross-reactive allergens belonging to the major food allergen groups. Cross-reactivity in allergy is a broad term used to define the ability of (secondary) allergen(s) to recognize IgE antibodies and/or invoke a cellular (T-cell, mast cell, or basophil) response in the body upon exposure, which has been already sensitized to a primary (initiator) allergen that shares 1 or more epitope with the secondary allergen. These shared regions are defined as cross-reactive epitopes. IgE cross-reactivity is often recognized when allergic symptoms arise to an allergen source without prior exposure. However, IgE cross-reactivity might be clinically manifest or irrelevant. IgE cross-reactivity can be defined as the relationship between 1 antibody and 2 or more allergens.6Aalberse R.C. Assessment of allergen cross-reactivity.Clin Mol Allergy. 2007; 5: 2Crossref PubMed Scopus (72) Google Scholar Sensitization occurs to a primary allergen via a TH2 response, leading to the generation of allergen-specific IgE antibodies.7Sampson H.A. O'Mahony L. Burks A.W. Plaut M. Lack G. Akdis C.A. Mechanisms of food allergy.J Allergy Clin Immunol. 2018; 141: 11-19Abstract Full Text Full Text PDF PubMed Google Scholar These IgE antibodies may be directed to several conformational and/or to linear epitopes on the allergen.8Aalberse R.C. Crameri R. IgE-binding epitopes: a reappraisal.Allergy. 2011; 66: 1261-1274Crossref PubMed Scopus (67) Google Scholar When the individual is later exposed to a food source containing homologous proteins/allergens via ingestion, inhalation, or contact, the preformed primary allergen-specific IgE antibodies are able to recognize these secondary allergens via cross-reactive epitopes, and may lead to cross-linking on basophils and mast cells, resulting in mediator release and subsequent clinical symptoms (Fig 1). The secondary allergen may be a complete or incomplete allergen in that it may or may not be capable of inducing primary allergic sensitization by itself (cosensitization).6Aalberse R.C. Assessment of allergen cross-reactivity.Clin Mol Allergy. 2007; 5: 2Crossref PubMed Scopus (72) Google Scholar,9Aalberse R.C. Assessment of sequence homology and cross-reactivity.Toxicol Appl Pharmacol. 2005; 207: 149-151Crossref PubMed Scopus (9) Google Scholar In some cases, the route of exposure may differ between the primary and secondary allergen. For example, primary sensitization to shrimp tropomyosin may occur via ingestion, but secondary exposure and cross-reactive IgE binding to dust mite tropomyosin occurs via inhalation.10Kamath S.D. Johnston E.B. Iyer S. Schaeffer P.M. Koplin J. Allen K. et al.IgE reactivity to shrimp allergens in infants and their cross-reactivity to house dust mite.Pediatr Allergy Immunol. 2017; 28: 703-707Crossref PubMed Scopus (19) Google Scholar In addition, the IgE antibody's binding affinity to the secondary allergen may be weaker as compared with that to the primary allergen, depending on the number of cross-reactive epitopes and binding affinity. All these factors, in addition to the physicochemical stability and amino acid sequence homology or structural homology of the secondary allergen, play a role in the clinical relevance of IgE cross-reactivity. T-cell cross-reactivity can be defined as the reaction of T cells to more than 1 peptide-MHC ligand.11Lee C.H. Salio M. Napolitani G. Ogg G. Simmons A. Koohy H. Predicting cross-reactivity and antigen specificity of T cell receptors.Front Immunol. 2020; 11565096Crossref Scopus (19) Google Scholar T-cell cross-reactivity is possible for several reasons including MHC binding promiscuity and degeneracy in peptide-TCR recognition as a mechanism that has evolved to recognize a wide range of external antigenic peptides.12Sewell A.K. Why must T cells be cross-reactive?.Nat Rev Immunol. 2012; 12: 669Crossref PubMed Scopus (298) Google Scholar However, in terms of allergenic T-cell cross-reactivity, the most likely cause and mechanism is sequence homology of the T-cell cross-reactive peptide residues among closely related allergen sources.13Westernberg L. Schulten V. Greenbaum J.A. Natali S. Tripple V. McKinney D.M. et al.T-cell epitope conservation across allergen species is a major determinant of immunogenicity.J Allergy Clin Immunol. 2016; 138: 571-578.e7Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar A cross-reactive T-cell epitope is able to stimulate memory T cells and induce subsequent IgE production (Fig 2). A well-known example is the Bet v 1 immunodominant T-cell epitope Bet v 1142-156, and its cross-reactivity to homologous peptides from PR-10–like food allergens from apple, peach, pear cherry, hazelnut, celery, and carrot.14Jahn-Schmid B. Radakovics A. Lüttkopf D. Scheurer S. Vieths S. Ebner C. et al.Bet v 1142-156 is the dominant T-cell epitope of the major birch pollen allergen and important for cross-reactivity with Bet v 1–related food allergens.J Allergy Clin Immunol. 2005; 116: 213-219Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,15Breiteneder H. Ebner C. Molecular and biochemical classification of plant-derived food allergens.J Allergy Clin Immunol. 2000; 106: 27-36Abstract Full Text Full Text PDF PubMed Scopus (486) Google Scholar The presence of this dominant peptide was also detected after ex vivo antigen processing and MHC class II presentation.16Mutschlechner S. Egger M. Briza P. Wallner M. Lackner P. Karle A. et al.Naturally processed T cell-activating peptides of the major birch pollen allergen.J Allergy Clin Immunol. 2010; 125 (8.e1-718.e2): 711-718Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Cross-reactive T-cell epitope peptides have also been shown to play a role in CD4+ memory T-cell survival, in absence of the primary priming allergen.17Nakamura Y. Takagi S. Suzuki M. Ito H. Murakami S. Ohta N. Survival of memory T cells specific for Japanese cypress pollen allergen is maintained by cross-stimulation of putative pectate lyases from other plants.Allergy. 2001; 56: 385-392Crossref PubMed Scopus (0) Google Scholar In the context of predicting T-cell cross-reactive epitopes among closely related allergens, the peptide sequence homology is known to play an important role; higher the homology, stronger the cross-reactivity.13Westernberg L. Schulten V. Greenbaum J.A. Natali S. Tripple V. McKinney D.M. et al.T-cell epitope conservation across allergen species is a major determinant of immunogenicity.J Allergy Clin Immunol. 2016; 138: 571-578.e7Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar However, the structural stability of closely related allergens may also play a role, which may not be associated with sequence homology, in the generation of homologous T-cell peptides, and subsequent T-cell cross-reactivity.18Kamath S.D. Scheiblhofer S. Johnson C.M. Machado Y. McLean T. Taki A.C. et al.Effect of structural stability on endolysosomal degradation and T-cell reactivity of major shrimp allergen tropomyosin.Allergy. 2020; 75: 2909-2919Crossref PubMed Scopus (10) Google Scholar The clinically relevant cross-reactive allergens belonging to the major food groups are summarized below, and a brief overview on the current knowledge on cross-reactive IgE- or T-cell epitopes provided (Fig 3). Peanut and soybean are the most significant allergen sources of the Fabaceae family and consequently the best characterized concerning cross-reactivity of their allergens. Sensitization to peanut can be associated with sensitization to other members of the Fabaceae family such as soy and lupine, with tree nuts, or with pollen. Among peanut-allergic children, up to 67% were sensitized to other legumes and up to 28% had confirmed allergy to at least 1 other legume.19Muller T. Luc A. Adam T. Jarlot-Chevaux S. Dumond P. Schweitzer C. et al.Relevance of sensitization to legumes in peanut-allergic children.Pediatr Allergy Immunol. 2022; 33e13846Crossref Scopus (2) Google Scholar,20Cousin M. Verdun S. Seynave M. Vilain A.C. Lansiaux A. Decoster A. et al.Phenotypical characterization of peanut allergic children with differences in cross-allergy to tree nuts and other legumes.Pediatr Allergy Immunol. 2017; 28: 245-250Crossref PubMed Scopus (29) Google Scholar Similarly, allergy to tree nuts is common among children with peanut allergy, with up to 86% having sensitization to tree nuts and up to 40% clinically confirmed tree nut allergy.21McWilliam V.L. Perrett K.P. Dang T. Peters R.L. Prevalence and natural history of tree nut allergy.Ann Allergy Asthma Immunol. 2020; 124: 466-472Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar All known peanut allergens were determined to comprise 85% of the total protein content of peanut, whereas seed storage proteins of the 2S albumin (Ara h 2, 6, and 7), the vicilin (Ara h 1), and the legumin (Ara h 3) protein families together accounted for 75%.22Hebling C.M. Ross M.M. Callahan J.H. McFarland M.A. Size-selective fractionation and visual mapping of allergen protein chemistry in Arachis hypogaea.J Proteome Res. 2012; 11: 5384-5395Crossref PubMed Scopus (18) Google Scholar In addition, the allergens of these 3 families have been identified as major allergens in other legumes and tree nuts. Consequently, frequent cosensitization of peanut-allergic individuals to other legumes and tree nuts has been interpreted by cross-reactive epitopes present in homologous allergens from the 3 protein families. Although, for the majority, the sequential IgE epitopes have been identified, their cross-reactivity was only rarely investigated. Apart from a conserved pattern of 8 cysteine residues, the sequence of Ara h 2 shows very low sequence identities (<36%) to 2S albumins from other legumes and tree nuts. However, their structural similarity has been proposed as the immunologic basis for the observed coallergies.23Dreskin S.C. Koppelman S.J. Andorf S. Nadeau K.C. Kalra A. Braun W. et al.The importance of the 2S albumins for allergenicity and cross-reactivity of peanuts, tree nuts, and sesame seeds.J Allergy Clin Immunol. 2021; 147: 1154-1163Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar Ara h 1 shows 39% to 53% sequence identities with vicilins from tree nuts and botanically related legumes. Using homology modeling, 5 surface-exposed epitopes of Ara h 1 have been predicted on the basis of the conformational similarity to be cross-reactive with Gly m 5, Jug r 1, Ana o 1, and Cor a 11.24Barre A. Sordet C. Culerrier R. Rance F. Didier A. Rouge P. Vicilin allergens of peanut and tree nuts (walnut, hazelnut and cashew nut) share structurally related IgE-binding epitopes.Mol Immunol. 2008; 45: 1231-1240Crossref PubMed Scopus (87) Google Scholar However, in inhibition assays with IgE-binding peptides from Ara h 1, 2, and 3 and corresponding peptides from walnut allergens (Jug r 1, 2, and 4), no relevant cross-reacting IgE antibodies could be detected in sera from peanut- and walnut-allergic patients.25Rosenfeld L. Shreffler W. Bardina L. Niggemann B. Wahn U. Sampson H.A. et al.Walnut allergy in peanut-allergic patients: significance of sequential epitopes of walnut homologous to linear epitopes of Ara h 1, 2 and 3 in relation to clinical reactivity.Int Arch Allergy Immunol. 2012; 157: 238-245Crossref PubMed Scopus (0) Google Scholar Similarly to IgE cross-reactive epitopes, T-cell cross-reactive epitopes between peanut and other seeds are poorly defined. In 4 of 5 patients with peanut and hazelnut coallergy, cross-reactive T-cell response was driven by cross-reactivity to Ara h 1 and 2, but the specificity of cross-reactive T-cell epitopes was not defined.26Glaspole I.N. de Leon M.P. Prickett S.R. O'Hehir R.E. Rolland J.M. Clinical allergy to hazelnut and peanut: identification of T cell cross-reactive allergens.Int Arch Allergy Immunol. 2011; 155: 345-354Crossref PubMed Scopus (0) Google Scholar Peanut oleosins (Ara h 10, 11, 14, and 15) might be a cause of IgE cross-reactivity to oil-contained seeds. The linear IgE epitope DKARDVKDRAKDYAG, localized in the C-terminal domain of Ara h 15 with high sequence identity to other seed-derived oleosins, was recognized by IgE from soybean- and rapeseed-allergic patient.27Schwager C. Kull S. Behrends J. Rockendorf N. Schocker F. Frey A. et al.Peanut oleosins associated with severe peanut allergy—importance of lipophilic allergens for comprehensive allergy diagnostics.J Allergy Clin Immunol. 2017; 140: 1331-1338.e8Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Peanut allergens belonging to the Bet v 1 (Ara h 8), the profilin (Ara h 5), the defensin (Ara h 12 and 13), and the cyclophilin (Ara h 18) protein families are mostly involved in pollen-associated food allergy. Furthermore, the nonspecific lipid transfer proteins (Ara h 9, 16, and 17) are involved in the so-called nonspecific lipid transfer protein syndrome.28Bublin M. Breiteneder H. Cross-reactivity of peanut allergens.Curr Allergy Asthma Rep. 2014; 14: 426Crossref PubMed Scopus (72) Google Scholar One IgE-binding surface area on Bet v 1 and Ara h 8, identified by using phage-displayed epitope mimics, was shown to be involved in IgE cross-reactivity to Gly m 4.29Mittag D. Batori V. Neudecker P. Wiche R. Friis E.P. Ballmer-Weber B.K. et al.A novel approach for investigation of specific and cross-reactive IgE epitopes on Bet v 1 and homologous food allergens in individual patients.Mol Immunol. 2006; 43: 268-278Crossref PubMed Scopus (70) Google Scholar Although cross-reactivity has been commonly recognized between members of the same protein family, several lines of evidence demonstrated IgE cross-reactivity between members of different protein families of seed storage proteins. It was demonstrated that IgE cross-reactive to Ara h 1, 2, and 3 comprised the major fraction of IgE specific to these allergens in sera from peanut-allergic patients.30Bublin M. Kostadinova M. Radauer C. Hafner C. Szepfalusi Z. Varga E.M. et al.IgE cross-reactivity between the major peanut allergen Ara h 2 and the nonhomologous allergens Ara h 1 and Ara h 3.J Allergy Clin Immunol. 2013; 132: 118-124Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar The cross-reactive IgE antibodies manifested identical gene rearrangements in unrelated individuals as well as high affinity and cross-reactivity to the peanut allergens.31Croote D. Darmanis S. Nadeau K.C. Quake S.R. High-affinity allergen-specific human antibodies cloned from single IgE B cell transcriptomes.Science. 2018; 362: 1306-1309Crossref PubMed Scopus (96) Google Scholar The 3 Ara h 2 epitopes implicated in this cross-reactivity (1: WLQGDRRCQSQLER, 2: SYGRDPYSPSQDPYS, and 3: PDRRDPYSPSPYDRR)30Bublin M. Kostadinova M. Radauer C. Hafner C. Szepfalusi Z. Varga E.M. et al.IgE cross-reactivity between the major peanut allergen Ara h 2 and the nonhomologous allergens Ara h 1 and Ara h 3.J Allergy Clin Immunol. 2013; 132: 118-124Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar have also been identified as immunodominant epitopes in different studies.32Suarez-Farinas M. Suprun M. Bahnson H.T. Raghunathan R. Getts R. duToit G. et al.Evolution of epitope-specific IgE and IgG4 antibodies in children enrolled in the LEAP trial.J Allergy Clin Immunol. 2021; 148: 835-842Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 33Suprun M. Sicherer S.H. Wood R.A. Jones S.M. Leung D.Y.M. Henning A.K. et al.Early epitope-specific IgE antibodies are predictive of childhood peanut allergy.J Allergy Clin Immunol. 2020; 146: 1080-1088Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 34Chen G. Shrock E.L. Li M.Z. Spergel J.M. Nadeau K.C. Pongracic J.A. et al.High-resolution epitope mapping by AllerScan reveals relationships between IgE and IgG repertoires during peanut oral immunotherapy.Cell Rep Med. 2021; 2100410Google Scholar The molecules named covalent heterobivalent inhibitors containing only 1 immunodominant epitope of Ara h 2 (DPYSPOHSDRRGAGSS) and 1 of Ara h 6 (QDRQ) yielded an almost complete inhibition of basophil degranulation to peanut extract in in vitro cellular assays with patients' sera.35Deak P.E. Kim B. Abdul Qayum A. Shin J. Vitalpur G. Kloepfer K.M. et al.Designer covalent heterobivalent inhibitors prevent IgE-dependent responses to peanut allergen.Proc Natl Acad Sci U S A. 2019; 116: 8966-8974Crossref PubMed Scopus (3) Google Scholar IgE- and T-cell cross-reactivities between Ara 1, 2, and 3 were also observed in mice.36Smit J.J. Pennings M.T. Willemsen K. van Roest M. van Hoffen E. Pieters R.H. Heterogeneous responses and cross reactivity between the major peanut allergens Ara h 1, 2,3 and 6 in a mouse model for peanut allergy.Clin Transl Allergy. 2015; 5: 13Crossref PubMed Google Scholar Primary soybean allergy is associated with sensitization to soybean vicilin Gly m 5 (7S globilin, β-conglycinin), legumin Gly m 6 (11S globulin, glycinin), 2S albumin Gly m 8, and the oil body–associated Gly m Bd 30K and Gly m Bd 28K. The seed storage proteins, Gly m 8, Gly m 5, and Gly m 6, are major contributors (80%) to the protein content of this seed and are recognized as potential diagnostic markers for severe allergic reactions to soybean.37Holzhauser T. Wackermann O. Ballmer-Weber B.K. Bindslev-Jensen C. Scibilia J. Perono-Garoffo L. et al.Soybean (Glycine max) allergy in Europe: Gly m 5 (beta-conglycinin) and Gly m 6 (glycinin) are potential diagnostic markers for severe allergic reactions to soy.J Allergy Clin Immunol. 2009; 123: 452-458Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar,38Ebisawa M. Brostedt P. Sjolander S. Sato S. Borres M.P. Ito K. Gly m 2S albumin is a major allergen with a high diagnostic value in soybean-allergic children.J Allergy Clin Immunol. 2013; 132 (-5): 976-978.e1Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Linear epitopes of Gly m 6.0201 (GSNILSGFAPEF) and Gly m 6.0501 (GSVLSGFSKHFL) overlapped with a previously identified epitope hot spot (HS#2) of legumins from peanut and tree nuts.39Saeed H. Gagnon C. Cober E. Gleddie S. Using patient serum to epitope map soybean glycinins reveals common epitopes shared with many legumes and tree nuts.Mol Immunol. 2016; 70: 125-133Crossref PubMed Scopus (25) Google Scholar However, further studies are necessary to confirm the cross-reactivity including inhibition assays and histamine release assays to confirm the ability of these epitopes to inhibit IgE and activate effector cells. In birch-endemic regions, soybean allergy is based on cross-reactivity between birch pollen allergen Bet v 1 and its related allergen Gly m 4 in soybean.40Mittag D. Vieths S. Vogel L. Becker W.M. Rihs H.P. Helbling A. et al.Soybean allergy in patients allergic to birch pollen: clinical investigation and molecular characterization of allergens.J Allergy Clin Immunol. 2004; 113: 148-154Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar Investigation of the conformational IgE epitope profile of soybean allergen Gly m 4 using Gly m 4–type model proteins harboring individual and multiple putative epitopes found 4 putative IgE-binding areas suitable to discriminate allergic and tolerant subjects.41Husslik F. Nurnberg J. Seutter von Loetzen C. Mews T. Ballmer-Weber B.K. Kleine-Tebbe J. et al.The conformational IgE epitope profile of soya bean allergen Gly m 4.Clin Exp Allergy. 2016; 46: 1484-1497Crossref PubMed Scopus (23) Google Scholar However, the study did not investigate how those epitopes are involved in cross-reactivity with Bet v 1. By a combination of different bioinformatics tools, predicted Gly m 4 T-cell epitopes AKADALFKAIEAYLL and ADALFKAIEAYLLAH42Zhou F. He S. Zhang Y. Wang Y. Sun H. Liu Q. Prediction and characterization of the T cell epitopes for the major soybean protein allergens using bioinformatics approaches.Proteins. 2022; 90: 418-434Crossref PubMed Scopus (1) Google Scholar share high sequence identity (80%) to the immunodominant Bet v 1 T-cell epitope TLLRAVESYLLAHSD" (aa 142-156), and thus could be responsible for cross-reactivity at the T-cell level.14Jahn-Schmid B. Radakovics A. Lüttkopf D. Scheurer S. Vieths S. Ebner C. et al.Bet v 1142-156 is the dominant T-cell epitope of the major birch pollen allergen and important for cross-reactivity with Bet v 1–related food allergens.J Allergy Clin Immunol. 2005; 116: 213-219Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In addition, Gly m 5 and Gly m Bd 30K cross-reactive epitopes have been described to be involved in reactions to a soybean protein formula in patients allergic to cow's milk (CM) (summarized by Bublin and Breiteneder3Bublin M. Breiteneder H. Cross-reactivities of non-homologous allergens.Allergy. 2020; 75: 1019-1022Crossref PubMed Scopus (7) Google Scholar). Three peptides on Gly m 5 and 4 peptides on Bos d 9 (α-casein [CN]) with a common core motif were identified using a Bos d 9 (α-CN)-specific mAb.43Candreva A.M. Ferrer-Navarro M. Bronsoms S. Quiroga A. Curciarello R. Cauerhff A. et al.Identification of cross-reactive B-cell epitopes between Bos d 9.0101 (Bos Taurus) and Gly m 5.0101 (Glycine max) by epitope mapping MALDI-TOF MS.Proteomics. 2017; 17Crossref PubMed Scopus (0) Google Scholar Recently, application of cross-reactive soybean allergen Gly m Bd 30K peptide NKIQDKVTIDGY comprising an immunodominant cross-reactive T-cell and IgG epitope was shown to prevent IgE-mediated milk sensitization in mice through the induction of blocking IgG.44Candreva A.M. Smaldini P.L. Cauerhff A. Petruccelli S. Docena G.H. A novel approach to ameliorate experimental milk allergy based on the oral administration of a short soy cross-reactive peptide.Food Chem. 2021; 346128926Crossref PubMed Scopus (7) Google Scholar The tree nut allergy prevalence varies from less than 1% to approximately 3%.21McWilliam V.L. Perrett K.P. Dang T. Peters R.L. Prevalence and natural history of tree nut allergy.Ann Allergy Asthma Immunol. 2020; 124: 466-472Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Walnut, hazelnut, cashew, pistachio, almond, Brazil nut, and macadamia are the typically reported tree nut allergen sources. Most of the patients with allergy to tree nut are sensitized to multiple nuts, but strong clinically relevant cosensitization was found only between highly botanically related cashew and pistachio as well as between walnut and pecan (summarized by Cox et al1Cox A.L. Eigenmann P.A. Sicherer S.H. Clinical relevance of cross-reactivity in food allergy.J Allergy Clin Immunol Pract. 2021; 9: 82-99Abstract Full Text Full Text PDF PubMed Google Scholar). Their concurrent allergies and extensive in vitro IgE cross-reactivity have been interpreted by the high sequence identities (≥70%) of their homologous allergens from the vicilin, legumin, or 2S albumin protein families. 2S albumins Ana o 1 from cashew and Pis v 3 from pistachio share 81% sequence identity. Using molecular modeling, a surface patch comprising 2 of the previously identified Ana o 3 linear IgE epitopes was predicted to be part of a conformational epitope responsible for cross-reactivity to Pis v 1.23Dreskin S.C. Koppelman S.J. Andorf S. Nadeau K.C. Kalra A. Braun W. et al.The importance of the 2S albumins for allergenicity and cross-reactivity of peanuts, tree nuts, and sesame seeds.J Allergy Clin Immunol. 2021; 147: 1154-1163Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar At the T-cell level, it has been demonstrated that cashew allergens Ana o 1 (vicilin) and Ana o 2 (legumin) share cross-reactive T-cell epitopes to pistachio and/or hazelnut but not to walnut.45Archila L.D. Chow I.T. McGinty J.W. Renand A. Jeong D. Robinson D. et al.Ana o 1 and Ana o 2 cashew allergens share cross-reactive CD4(+) T cell epitopes with other tree nuts.Clin Exp Allergy. 2016; 46: 871-883Crossref PubMed Scopus (24) Google Scholar In Central-Northern Europe, hazelnut, walnut, and almond are often involved in the so-called pollen-food allergy syndrome due to the cross-reactivity of Bet v 1–specific IgE to hazelnut Cor a 1.04, walnut Jug r 5, and almond Pru du 1.46Uotila R. Kukkonen A.K. Pelkonen A.S. Makela M.J. Cross-sensitization profiles of edible nuts in a birch-endemic area.Allergy. 2016; 71: 514-521Crossref PubMed Scopus (43) Google Scholar,47Kabasser S. Crvenjak N. Schmalz S. Kalic T. Hafner C. Dubiela P. et al.Pru du 1, the Bet v 1-homologue from almond, is a major allergen in patients with birch pollen associated almond allergy.Clin Transl Allergy. 2022; 12e12177Crossref PubMed Scopus (0) Google Scholar A possible cross-reactive epitope might be located in the highly conserved glycine-rich region.47Kabasser S. Crvenjak N. Schmalz S. Kalic T. Hafner C. Dubiela P. et al.Pru du 1, the Bet v 1-homologue from almond, is a major allergen in patients with birch pollen associated almond allergy.Clin Transl Allergy. 2022; 12e12177Crossref PubMed Scopus (0) Google Scholar Similar to peanuts, cross-reactive epitopes betw